1. Field of the Invention
This invention is in the general field of pharmaceuticals, and relates in particular to formulations for drugs that benefit from a prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and from an enhanced opportunity for absorption in the stomach and upper GI tract rather than the lower portions of the GI tract. One goal of this invention is to release drugs in a controlled manner over an extended period of time. Another goal is to extend the time of delivery into the stomach of drugs that are preferentially absorbed high in the GI tract, and thereby to achieve a greater and more prolonged therapeutic effect with potentially diminished side effects. This will reduce the frequency of administration required and achieve a more efficient use of the drugs and a more effective treatment of local stomach disorders. A third goal is to minimize both lower-GI tract inactivation of the drug and drug effects on the lower intestinal flora.
2. Description of the Prior Art
Many drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner have a lower level of side effects and provide their therapeutic effects without the need for repeated dosages, or with a low dosage frequency. Localization of the drug delivery in the stomach is an advantage for the treatment of local disorders of the stomach such as esophageal reflux disease, for the eradication of ulcer-causing bacteria in the gastric mucosa, and for the treatment of disorders that require sustained antacid action. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited. Under normal or average conditions, for example, material passes through the small intestine in as little as 1 to 3 hours. For drugs that are absorbed almost exclusively in the small intestine, such as captopril and the cephalosporins, this short contact time limits the bioavailability of these drugs, particularly when the drugs are administered in a controlled-release dosage form.
The passage of matter through the stomach can be delayed in the normal digestive process by the physiological condition that is variously referred to as the digestive mode, the postprandial mode, or the xe2x80x9cfed modexe2x80x9d (the latter term is used in the remainder of this specification for convenience). When the stomach is not in this mode, it is in the interdigestive or xe2x80x9cfastingxe2x80x9d mode. The difference between the two modes lies in the pattern of gastroduodenal motor activity.
In the fasting mode, the stomach exhibits a cyclic activity called the interdigestive migrating motor complex (IMMC). This activity occurs in four phases:
In Phase I, which lasts 45 to 60 minutes and is the most quiescent, few or no contractions occur.
In Phase II, irregular intermittent sweeping contractions occur that gradually increase in magnitude.
In Phase III, intense bursts of peristaltic waves appear in both the stomach and the small bowel. This lasts for 5 to 15 minutes.
Phase IV is a transition period of decreasing activity which lasts until the next cycle begins.
The total cycle time is approximately 90 minutes, and the contents of the stomach are swept out by the powerful peristaltic waves that occur during Phase III. Phase III of the IMMC thus functions as an intestinal housekeeper, sweeping swallowed saliva, gastric secretions, food particles, and particulate debris to the small intestine and colon, and preparing the upper tract for the next meal while preventing bacterial overgrowth. Pancreatic exocrine secretion of pancreatic peptide and motilin also cycle in synchrony with the motor pattern.
The fed mode is induced by nutritive elements immediately after food ingestion, and begins with a rapid and profound change in the motor pattern of the upper gastrointestinal (GI) tract, the change occurring over a period of 30 seconds to one minute. The change occurs almost simultaneously at all sites of the GI tract, before the stomach contents have reached the distal small intestine. Once the fed mode is established, the stomach generates 3-4 continuous and regular contractions per minute, similar to those of the fasting mode but with about half the amplitude. The pylorus is partially open, causing a sieving effect in which liquids and small particles flow continuously from the stomach into the intestine while indigestible particles greater in size than the pyloric opening are retropelled and retained in the stomach. This sieving effect thus causes the stomach to retain particles exceeding about 1 cm in size for approximately 4 to 6 hours.
The minimum particle size that will be retained in the stomach is thus substantially smaller in the fed mode than in the fasting mode. Particles large enough to be retained in the fasting mode are too large for practical administration in most patients. Particles of a smaller particle size can be retained in the stomach if they are administered to a patient who is in the fed mode, and this serves as an effective and feasible means of prolonging the residence time of these particles in the stomach.
Whether the subject is in the fed mode or the fasting mode, a further means of prolonging the residence time of particles in the stomach is to use particles that are initially small enough for comfortable ingestion but swell to a larger size upon contact with the gastric fluid in the stomach. The swelling can occur as a result of hydration of the particle material upon absorption of water from the gastric fluid, or as a result of gas generation, such as carbon dioxide for example, by contact of gastric fluid with the dosage form, the gas generation occurring in a membrane bag or otherwise within the dosage form. Swelling can also be achieved by placing a large tablet in a compressed condition under mechanical tension inside a small capsule which will release the tablet when the capsule contacts gastric fluid, permitting the released tablet to expand to its full relaxed size.
Disclosures of oral dosage forms that swell to sizes that will prolong the residence time in the stomach are found in U.S. Pat. No. 5,007,790 (xe2x80x9cSustained-Release Oral Drug Dosage Form;xe2x80x9d Shell, inventor; Apr. 16, 1991), U.S. Pat. No. 5,582,837 (xe2x80x9cAlkyl-Substituted Cellulose-Based Sustained-Release Oral Drug Dosage Forms;xe2x80x9d Shell, inventor: Dec. 10, 1996): U.S. Pat. No. 5,972,389 (xe2x80x9cGastric-Retentive Oral Drug Dosage Forms for the Controlled Release of Sparingly Soluble Drugs and Insoluble Matter;xe2x80x9d Shell et al., inventors; Oct. 26, 1999); International (PCT) Patent Application WO 98/55107 (xe2x80x9cGastric-Retentive Oral Drug Dosage Forms for Controlled Release of Highly Soluble Drugs;xe2x80x9d Shell et al., inventors; publication date Dec. 10, 1998); and International (PCT) Patent Application WO 96/26718 (xe2x80x9cControlled Release Tablet;xe2x80x9d Kim, inventor: publication date Sep. 6, 1996).
Even with swelling, a certain proportion of particles can pass through the pylorus regardless of whether the subject is in the fed mode or the fasting mode, if the particles become oriented when in the vicinity of the pylorus such that their longest dimension is in alignment with the pyloric axis. This is particularly true of tablets or caplets (cylindrical tablets with rounded ends) that are elongated in shape to facilitate swallowing. When dosage forms such as these swell due to imbibition of water, one dimension may achieve a length great enough to exceed the pyloric opening while the others may be significantly smaller. The dosage form will thus be retained in the stomach only if the form is oriented with the long dimension transverse to the pyloric opening. Accordingly, for a certain percentage of the administered units of these swellable forms, prolonged retention in the stomach is not achieved and the beneficial effect of the swelling is lost. There is thus only a limited assurance that the swelling will result in gastric retention of the dosage form.
It has now been discovered that by using a solid water-swellable dosage form of a particular shape, the proportion of these dosage forms that escapes through the pylorus due to a fortuitous orientation at the pylorus can be reduced or eliminated entirely while still having a dosage form that is easily swallowed. The shape that achieves this result is a non-circular and non-spherical shape which, when projected onto a planar surface, has two orthogonal axes of different lengths, the longer axis being at most 3.0 cm in length, preferably 2.5 cm or less in length, when the dosage form is in the unswollen state, and the shorter axis being long enough to achieve a length of at least 1.2 cm, preferably at least 1.3 cm, within the first one hour, and preferably thirty minutes of swelling time. In addition to enhancing gastric retention, the non-circular and non-spherical shape render the tablets of this invention convenient to swallow. The tablets are also smaller than many tablets of the prior art that were designed for a similar effect, and this offers an advantage for people who suffer from a psychological difficulty when attempting to swallow a tablet.
The improvement offered by this invention provides benefits to many types of drugs, including those whose activity is lessened for various reasons once they pass into regions of the gastrointestinal tract that are downstream of the stomach and upper regions of the small intestine, as well as those that give rise to detrimental physiological effects in these regions. These drugs range in solubility from those that are only sparingly soluble in water to those that are highly soluble.
The dosage form is a swellable body, preferably a polymeric matrix in which the drug is dispersed. The polymer is swellable upon imbibition of water and thus upon contact with gastric fluid when reaching the stomach. In certain embodiments of the invention, the polymer is erodible as well. When an erodible polymer is used, the polymer is one whose erosion rate is substantially slower than the swelling rate. In some cases, the erosion of the polymer is used as a means of releasing the drug to the stomach, and at times a combination of erosion and dissolution/diffusion is used.
In certain embodiments of this invention, the dosage form is a multilayered tablet in which one or more of the layers swells while the others do not. In further embodiments of the invention, the dosage form is a tablet with a core surrounded by a shell, and the core swells while the shell remains relatively dimensionally stable, or vice versa.
These and other features, characteristics, and embodiments of the invention will be apparent from the description that follows.